Triple negative breast cancer (TNBC) is the breast tumor subtype that is negative for the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Due to its aggressive nature and the lack of effective targeted therapies, patients with TNBC generally have a poorer prognosis than patients with the most common breast cancer subtype, luminal A (ER+ or PR+, HER2-). The overall 5-year survival rate for TNBC patients is at least 10% lower than that for luminal A patients. Furthermore, TNBC tends to strike premenopausal black women more frequently than others. Our long-term goal is to better understand the etiology of TNBC so that we can develop targeted approaches that reduce its occurrence on a population-wide scale. Gene expression studies indicate luminal A tumors are associated with ER signaling, whereas the majority of TNBCs are characterized by a basal-like molecular profile, typically overexpressing genes involved in cell proliferation and differentiation. Based on the clinical and molecular differences between TNBC and luminal A, we hypothesize that the risk profiles for these two subtypes are likely to be different. Previous studies have shown that established hormone-related risk factors for breast cancer overall (e.g., reproductive factors) are associated with luminal A. However, the TNBC risk profile remains vague due to the small number of TNBC cases in the majority of published single studies, and the limited risk factor data available for published collaborative or pooled analyses. The objective of this proposal is to identify risk factors for TNBC, compare their contributions to the likelihood of developing TNBC and luminal A, and determines if race or menopausal status modifies any overall main effect for TNBC or any heterogeneity detected between TNBC and luminal A. We have access to existing data collected by three large population-based case-control studies of women aged 20-64 years. The data include case participants' ER/PR/HER2 status and detailed information about various exposures for case and control participants. These studies will supply us with both a large number of TNBC cases (n=566) and detailed information for an extended list of risk factors, which are not available in most previous studies. Factors of interest are 10 known and suspected risk or protective factors identified when breast cancer was considered as a single disease. They include menstrual/reproductive history, oral contraceptive use, menopausal hormone therapy use, body size measures and their changes over time, race, breast cancer family history, recreational physical activity, alcohol consumption, cigarette smoking, and prenatal factors. The large sample of TNBC cases, the extended list of potential breast cancer risk factors, and the variety of study participants with respect to race (white, black) and age (pre- and post-menopausal), all provide the resources needed to carry out this study. Successful completion of this project will provide new insight into the etiology of TNBC, which could lead to novel targeted approaches to the prevention of TNBC on a population-wide scale.